PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Trilateral neuroblastoma occurs when both eyes are involved with retinoblastomas and there is a pinealblastoma in the pineal gland.
PERSPECTIVE AND PATTERNS OF SPREAD
Retinoblastoma is a hereditary malignancy and occurs in approximately 1 in 20,000 live births. There is no known difference in the incidence between whites and blacks, between males and females, or in children in various parts of the world (Fig. 58.1). Thirty percent of retinoblastomas are bilateral, and all bilateral tumors are germinal. Forty percent of all retinoblastomas are germinal (i.e., 25% of all unilateral tumors are germinal). In these cases, there is a 100% chance of an autosomal-dominant pattern of hereditary transmission to the next generation, as well as a lifelong significant risk of develop ment of a second, nonocular malignancy (85%). More than 90% of retinoblastoma cases are diagnosed before age 5 years. The median age at diagnosis is 14 months for bilateral cases and 23 months for unilateral tumors. There is a 5% association with other congenital defects, of which mental retardation is the most common. In the syndrome designated Dq-1, half of the patients have retinoblastoma, as well as a high incidence of other defects, including psychomotor retardation, skeletal abnormalities, congenital heart disease, and other eye defects. Spontaneous regression occurs in 1% of all retinoblastoma patients. This has been attributed to the tumor's outgrowing its vascular supply and becoming infarcted and necrotic.
Retinoblastoma has been documented to result from a genetic mutation. Retinoblastoma behaves like an autosomal-dominant syndrome with >90% penetrance, but the abnormal tumor-producing mutant allele is recessive. Seventy percent of retinoblastomas present as unilateral tumors. In all the bilateral and in 25% of the unilateral presentations, a germinal mutation affecting all cells in the body has occurred. Despite the high occurrence rate of germinal mutations (40% of cases), only 12% of patients have a positive family history; the other 88% represent the first germinal mutation in the famil.
Retinoblastoma conforms to the two-hit Knudson hypothesis, in which two chromosomal mutational events are necessary to cause cancer. In the hereditary form, the mutational event affects a germ cell and thus all cells in the body, whereas in nongerminal cell cases, a single retinal cell is affected. The normal allele at the retinoblastoma locus is believed to act as a controller gene or suppressor of the malignant retinoblastoma growth. Thus, both alleles must be lost before malignant growth can ensue. In the hereditary cases, all cells have lost one normal allele, and the chance of several retinal cells losing the second allele is quite high, resulting in bilateral or multicentric tumor growth at an earlier age (median, 14 months). In the nonhereditary or somatic form, one retinal cell has lost one allele and must lose the second before a unicentric, unilateral tumor arises, usually at a later age (median, 23 months). Thus, in nongerminal cases, the chance of bilateral mutations (two hits) on two separate retinal cells is low, and the chance that a bilateral tumor would be nongerminal or somatic is equally low. Because 50% of the offspring of germinal retinoblastoma patients are affected, prenatal or presymptomatic diagnosis is crucial. A few laboratories have developed diagnostic tests to identify the retinoblastoma gene in this group of patients. Detection of the gene in the 15% of patients with unilateral disease that have the germinal mutation is also important because they carry a lifelong risk of secondary malignancies. Healthy parents who have a single affected child can expect an attack rate of 6% among their other offspring. An unaffected sibling of a child with sporadic retinoblastoma, like one of his parents, may be a carrier; however, the risk is extremely low (>1%). If retinoblastoma occurs more than once in a given pedigree, there is a 40% to 48% chance that the affected members of this pedigree will have offspring with retinoblastoma. The unaffected members have a chance of only 5% to 20%.
Figure 58.1 | Retinoblastoma. A. The white pupil (leukocoria) in the left eye is the result of an intraocular retinoblastoma. B. This surgically excised eye is almost filled by a cream-colored intraocular retinoblastoma with calcified flec
Figure 58.2 | Patterns of spread. Primary cancers of the retina are color coded for progression: T0, yellow; T1, green; T2, blue; T3, purple; T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 58.1).
History of prematurity and oxygen therapy may predispose the infant, but the likely presenting sign is “leukoria” or recognition of “white reflex” in the pupil of the eye instead o red at angles of light or photographs. Binocular indirect ophthalmoscopy is an important diagnostic exam to verify the presence of a tumor with whitish color due to calcificatio (Fig. 58.1).
The tumor spreads readily within the eye (Fig. 58.2; Table 58.1). Trilateral retinoblastoma occurs when both eyes are involved and pineoblastoma occurs in the pineal gland. This rare but interesting combination illustrates that the pineal or third eye shares the same developmental anlage as the retina. This diagnosis must be considered in a patient with bilateral retinoblastoma who subsequently develops headache or lethargy.
Early recognition, especially in the hereditary form, allows for conservation of the eye using modern radiation techniques that conform to the tumor shape and size while sparing the eye. As the retinoblastoma advances and fills the eye globe an invades the optic nerve, the surgical enucleation of the eye globe and optic nerve leads to a pathologic staging that is most important.
Trilateral retinoblastomas are rare (2% to 5%): Bilateral retinoblastomas in addition to ectopic retinoblastomas of the pineal gland. This atypical presentation can begin as an increase in intracranial pressure with lethargy, vomiting, and ataxia.
OVERVIEW OF HISTOGENESIS AND HISTOPATHOLOGY
The embryogenesis of the eye has no endoderm and is tripartite: it is the neural ectoderm that is the focus for the epithelium of retina and optic nerve and partly of vitreous body that is our concern. The retina is the most complex tissue of the eye and consists of numerous cell layers (six) (Fig. 58.4B) and cell populations (10). It is similar in its organization to the cerebral cortex (Fig. 58.4A).
The analogy is essential to understanding the behavior of the retinoblastoma and its spread pattern into the optic nerve and ultimately into the subarachnoid space. The eye is unlike other cranial nerves, which are more akin to peripheral nerves. The optic nerve is more vulnerable to invasion of the central nervous system (CNS) than other forms of perineural invasion of cranial nerves. The optic nerve is a projection of the forebrain, and its fibrous covers are an extension of the meninges its most innermost layer is the neural retina. The sclera is penetrated by the optic nerve that forms the optic disc and is the lamina cribrosa or cribriform plate, sometimes referred to as a blind spot. Thus, the importance in the TNM classification i to the distance to optic nerve because this is the gateway to CNS invasion and spread. Once the retinoblastoma crosses the lamina cribrosa, it has invaded the CNS. Retinoblastomas have three growth patterns: endophytic (into the vitreous), exophytic (between sensory and pigmented layer, which leads to retinal detachment), and diffuse multicentric—seeding and snowballing.
Figure 58.3 | Retinoblastoma. Light microscopic view of a retinoblastoma showing Flexner–Wintersteiner rosettes characterized by cells that are arranged around a central cavity.
Retinoblastoma usually arises from the posterior portion of the retina and consists of small, closely packed, round or polygonal cells with dark-staining nucleus and scanty cytoplasm (Table 58.2). In many cases, the tumor cells are arranged in rosettes, but their absence does not necessarily exclude this diagnosis. Histopathologic classification of retinoblastoma permits a certain amount of separation between more- and less-differentiated tumor varieties. The more-differentiated tumors show small rosettes that are believed to represent differentiated spongioblasts (neuroepitheliomas). The tumor often outgrows its blood supply. Areas of necrosis are common and are responsible for the formation of calcium deposits. Rarely, the tumor may become so necrotic as to destroy itself entirely, giving rise to the rare instance of spontaneous regression. The necrotizing tendency of the tumor is one of the factors responsible for the occasional intense ocular inflammation that may be highly misleadin clinically.
Layers of the retina, including the interrelationships of the neurons and the supporting cells, are variously defined a many different types of neurons and multiple synapses but are classified in three categories: (i) photoreceptors—retinal rods and cones, (ii) conducting neurons—bipolar and ganglion cells, and (iii) association with other neurons—horizontal, centrifugal amacrine supporting cells. The ultrastructure of the rod and cone is an (i) inner fibe, (ii) an inner segment, and (iii) an outer segment (Fig. 58.4).
HISTOGENESIS
Figure 58.4 | A. Cerebral cortex. Gray matter. Stain: silver impregnation (Cajal's method). Low magnification. B. Layers of the choroid and retina (detail). Stain: hematoxylin and eosin. High magnification
SUMMARY OF CHANGES SEVENTH EDITION AJCC
Clinical Classification (Fig. 58.5A; Table 58.3)
• The definitions of T1–T4 were modifie
• The definitions for M1 were modifie
CLINICAL
Figure 58.5 | Definition of TNM. A. Clinical. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
Pathologic Classification
• Minor modifications were made to the definitions for pT2–pT4 (Fig. 58.5B).
• The definitions for pM1 were modifie
Other
• A description of proper processing of the enucleated retinoblastoma globe for pathological examination was added.
• Definitions of the T stage progression can be described as
• Minimal T1 Focal
• Moderate T2 Massive
• Severe T3 Massive
• Extraocular T4 Massive
There is variation in descriptors from the sixth to the seventh edition.
In pathologic staging, the following definitions have bee added:
Artifactual invasion: cluster of tumor cells in open spaces between intraocular and extraocular spaces.
True invasion: one or more solid clusters fills/replaces choroi with pushing borders.
Focal choroidal: solid clusters ≤3 mm diameter.
Massive choroidal: solid clusters ≥3 mm diameter.
NB: There are numerous details to fixation sampling of th enucleated eye globe/optic nerve anterior-posterior in a “bread loaf” fashion.
PATHOLOGIC
Figure 58.5 | B. Pathologic. TNM staging criteria are color coded bars for T advancement: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red.
TNM STAGING CRITERIA
T-ONCOANATOMY
The retina is the innermost layer of the eye, and its posterior (75%) portion is photosensitive and is stimulated by light. Anteriorly, it ends at the ora serrata. The photoreceptor cells are rods and cones. Leaving the retina are nerve fibers tha form the optic disc and nerve and pass signals to the brain. There are sight strata of cells; in addition to the optic disc, there is the macula and an array of retinal arterioles and venules that characterize the eye grounds (Fig. 58.6).
Figure 58.6 | A. Whole eye (sagittal section). Stain: hematoxylin and eosin. Low magnification. B. Retina, choroid, and sclera (panoramic view). Stain: hematoxylin and eosin. Medium magnification
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The eye globe is immunologically privileged and has no lymphatics or regional lymph nodes.
M-ONCOANATOMY
The lesion can seed itself throughout the interior of the eye and include the iris and anterior chamber (Fig. 58.7). Distant spread of retinoblastoma commonly occurs along the optic nerve. Here the tumor can spread readily along the meningeal spaces of the optic sheath and soon reach the subarachnoid space and seed out into the cerebrospinal fluid. Distant sprea can also occur though the bloodstream, most commonly to bone, lungs, and liver. The causes of death in this tumor are interesting. More than 90% of the patients have intracranial involvement; in almost 50% of all deaths, disease is confine to the cranial cavity and spinal cord; the remaining half have distant metastases. Distant metastasis occurs with equal incidence (~50%) of spread to lymph nodes, skull bones, distant bones, and viscera.
Figure 58.7 | M-oncoanatomy of the eye. The choroid is drained by posterior ciliary veins, and four to five vorticose veins drai into the ophthalmic veins.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Examination under anesthesia is most desirable, and if simple orbital radiographs show calcification in the childs globe, it is pathognomonic for retinoblastoma (Table 58.4). Enhanced computed tomography is the preferred cross-sectional imaging, although magnetic resonance imaging is complementary for extraocular soft tissue extension and especially to assess for optic nerve invasion. With multiple lesions, ultrasound identification of their location is done with detailed retinal drawings. In bilateral cases, each eye should be staged separately. Distance of tumor from disc, fovea, and ora serrata should be noted in millimeters or estimated in terms of size of optic nerve disc (e.g., 1.5 × 1 or 2, etc.).
Pathologic Staging
If the eye is sacrificed and enucleated, tumor size, invasion o optic nerve, and margins, if there is extraocular spread, need notation.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
Clinically significant
• Extension evaluated at enucleation
• RB gene mutation
• Positive family history of retinoblastoma
• Primary globe-sparing treatment failure
• Greatest linear extent of choroid involved by choroidal tumor invasion*
CANCER STATISTICS AND SURVIVAL
The eye and orbit only account for 2,750 new diagnoses, excluding carcinomas of the eyelids. Deaths attributed to ocular malignancy are 10% of the entire group (240). Some of the most elegant proton and three-dimensional conformal radiation stereotactic techniques allow for cure of choroidal melanomas and retinoblastoma with preservation of vision, the majority with eye preservation (Table 58.5). Survival remains impressive; 90% achieve long-term survival.
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 566.
• Retinoblastomas are highly curable; with radiation, >90% local tumor control is achieved with vision conservation. Those that relapse can still be cured by enucleation.
• In Africa and Asia, retinoblastoma is the most common primary intraocular malignancy.
